HMG-CoA reductase inhibitors are commonly referred to as “statins”. Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease by taking the place of HMG-CoA in the enzyme enabled through the similarity of statins and HMG-CoA on a molecular level. By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver. Several statins have been discovered and synthetic routes for their production have been established. Among the synthesizable statins there are Rosuvastatin, Pitavastatin, Cerivastatin, Lovastatin, Atorvastatin, Fluvastatin, Simvastatin and Pravastatin. Due to the complicated molecular structures of these chiral compounds multi step protocols with certain key intermediates are common for their preparation.
In the synthesis of Rosuvastatin and its pharmaceutically acceptable salts N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (PMDBR), N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (PMDOH); N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethanesulfonamide (PMDME); N-(4-(4-fluorophenyl)-5-(formyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (PMDCHO) and (E)-N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-en-1-yl)pyrimidin-2-yl)-N-methylmethanesulfonamide (PMDOPEN) are possible intermediates. Rosuvastatin calcium, chemically described as bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt, is a synthetic lipid-lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoA Reductase inhibitor). Rosuvastatin calcium is used in the treatment of hypercholesterolemia and mixed dyslipidemia.
EP 521471 A1 discloses Rosuvastatin and a process for its preparation, among others by a process comprising a step of preparing N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide by reduction of a suitable ester derivative thereof with diisobutylaluminium hydride (DIBAL-H) as a reduction reagent.
In the synthesis of Pitavastatin and its pharmaceutically acceptable salts 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline (PTVBR), (2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methanol (PTVOH); 2-cyclopropyl-4-(4-fluorophenyl)-3-methylquinoline (PTVME); 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde (PTVCHO) and (E)-3-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)acrylaldehyde (PTVOPEN) are possible intermediates. Pitavastatin calcium, chemically described as bis[(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoic acid] calcium salt, is a synthetic lipid-lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoA Reductase inhibitor). Pitavastatin calcium is used in the treatment of hypercholesterolemia and mixed dyslipidemia.

Furthermore, WO2008/059519 A2 also describes the preparation of Rosuvastatin via N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide as intermediate obtained by reduction of a suitable ester (PMDCO2R) thereof by means of DIBAL-H.
International patent application WO2007/017117 A1 discloses the preparation of Rosuvastatin via N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide as the intermediate. This intermediate is prepared by nucleophilic substitution of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide by means of HBr as the source of nucleophile.
A process for preparing 2-amino-4-(4-fluorophenyl)-6-alkylpyrimidine-5-carboxylates (PMDCO2R) is described in PCT Pat. Appl. WO 2001/004100, 2001:

A process for preparing aminopyrimidine compounds is disclosed in PCT Pat. Appl. WO 2003/006439, 2003:

A synthesis of PMDCHO without application of PMDOH disclosing also the preparation of the diketone DK is described in Eur. J. Org. Chem. 2008, 847-853:

A method for the preparation of 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine (PMDCHO) is disclosed in PCT Pat. Appl. WO 2008/151510, 2008:

A preparation of (E)-N-(4-(4-fluorophenyl)-5-(3-hydroxyprop-1-enyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (MCALDKOH) and aldehyde derivative (E)-N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methylmethanesulfonamide (PMDOPEN) starting from N-(4-(4-fluorophenyl)-5-(formyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (PMDCHO) is described in patent literature under WO 2006100689, WO 2008053334, WO 2008072078 and IP.com Journal, 6(12B), 30; 2006 including Wittig or Wittig-Horner-Emmons reactions:

A preparation of (E)-N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methylmethanesulfonamide (PMDOPEN) is disclosed in WO 2007/007119 A1 including Suzuki coupling and subsequent reduction with DIBALH:

It is known from the art that PMDBR, PMDOH, PMDCHO and PMDOPEN can be used as key intermediates for the preparation of Rosuvastatin as shown in the scheme below:

PMDBR and PMDOH can be used for the preparation of PMD phosphine oxides, phosphonium salts and phosphonate esters.
A method for the preparation of Pitavastatin is disclosed in Tetrahedron Lett. 1992, 33, 7525-7526, and includes HWE olefination of Pitavastatin phosphine oxide derivatized heterocycle with acetonide protected side chain:

Synthesis of Pitavastatin via cross-coupling reaction is disclosed in Tetrahedron Lett. 1993, 34, 8263-8266, and in Tetrahedron Lett. 1993, 34, 8267-8270.
A method for the preparation of Pitavastatin via epichlorohydrin is described in Tetrahedron: Asymmetry 1993, 4, 201-204.
Synthesis of Pitavastatin heterocycle and Pitavastatin molecule assembly via aldol condensation reaction is disclosed in Bioorg. Med. Chem. Lett. 1999, 9, 2977-2982, and Bioorg. Med. Chem. 2001, 9, 2727-2743:


PCT application WO 2003/064382 describes a method for preparation of Pitavastatin by asymmetric aldol reaction, in which titanium complex is used as a catalyst.
HWE route to Pitavastatin by utilization of 3-formyl substituted Pitavastatin heterocycle is disclosed in Helv. Chim. Acta 2007, 90, 1069-1081:

Methods for preparation of Pitavastatin heterocycle derivatives are described in Bull. Chem. Soc. Jpn. 1995, 68, 364-372, Heterocycles 1999, 50, 479-483, Lett. Org. Chem. 2006, 3, 289-291, and in Org. Biomol. Chem. 2006, 4, 104-110, as well as in the international patent applications WO 95/11898 and WO 2004/041787.
WO 95/11898 and Bull. Chem. Soc. Jpn. 1995, 68, 364-372 disclose synthesis of PTVBR from PTVOH with PBr3:
